Abstract Knowledge of tissue oxygen level has enormous clinical significance in the diagnosis, prognosis, and treatment of several pathologies including cardiovascular disease, cancer, and wound healing. However, there is an unmet need for devices that can measure tissue oxygen in patients with a reasonable degree of accuracy, reliability, and robustness. Although a number of methods are considered applicable for oxygen measurements in patients, they lack the ability to make repeated measurements to monitor temporal changes during or post-therapy. Electron paramagnetic resonance (EPR)-based oximetry offers certain unique advantages over other methods, including high accuracy, high sensitivity to pO2 and high functional specificity. Unfortunately, the use of EPR-based techniques for clinical purposes still needs to address a number of fundamental issues, most notably the restrictions that arise from existing hardware. Most conventional EPR systems are large, bulky units with restrictive spacing between the magnet poles. Importantly, patients must be brought to the EPR facility for oxygen measurements. Hence, considerable changes in EPR hardware are necessary to make this technology more appealing and available by bedside or at treatment site from a clinical standpoint. The overall goal of this exploratory project is to develop a highly innovative miniature EPR device capable of repeated monitoring of deep tissue pO2 in patients. We propose to construct a unique self- contained compact EPR sensor system, called implantable oxygen sensor that can be used on site in the clinic. In contrast to the existing EPR system, which requires a large external magnet, our approach will use an ultra-small permanent magnet, which will be integrated within a resonator holding the oxygen-sensing probe. The all-in-one implantable unit will be of 2-mm diameter and 6-mm length and will be driven by a novel compact spectrometer, based on state-of-the-art field programmable gate array (FPGA) electronics. The specific aims of the two-year project are: (i) To construct a miniature EPR sensor using permanent magnets, loop-gap resonator, and oxygen- sensing crystal embedded in a silicone polymer attached to a compact, simple and affordable pulse EPR spectrometer; (ii) To validate the EPR sensor performance in vitro and in vivo using animal model. This unique device will enable continuous on-site and real-time monitoring of deep- tissue pO2 and may become a vital tool for clinical use to optimize various therapies for improving treatment outcomes.